tbuckley/cabot-search huggingface dataset:
Abstract 3680: Distinctive metabolomics profiles associated with African American current smokers who have high aggressive prostate cancer
Authors: Se-Ran Jun, L. Joseph Su, Eryn Matich, Ping-Ching Hsu
Journal: Cancer Research (2022)

Abstract Background: Smoking has not been an established risk factor for prostate cancer (PCa), and has not been emphasized in PCa prevention. However, recent studies have shown increasing evidence that there is a higher risk of biochemical recurrence, PCa mortality, and metastasis among current smokers, presenting an urgent need in re-evaluating the association between smoking and aggressive PCa. This study aimed to determine whether smoking increase the likelihood of developing a more aggressive prostate cancer. Methods: Equal numbers of African Americans (AAs) and European Americans (EAs) by smoking status (never/former/current) matched with PCa aggressiveness, BMI, 5-year age group, and year of baseline recruitment, totaling 480 participants, were included in the metabolomics study. For metabolomics analysis, fold change and BH-adjusted p-value from t-test adjusted for age for univariate analysis, and PCA adjusted for age and PLS-DA supervised statistical analysis for multivariate analysis were employed to decipher the underlying metabolomic patterns, and identify significantly dysregulated metabolites for the variables of interest. Results: AA participants were significantly younger (mean=61.4, SD=7.7) compared with EAs (mean=63.5, SD=7.5). Current smokers had a 2.4 times higher risk of high aggressive PCa. When stratified by race, the risk diminished for EAs but increased for AAs. Global metabolic profiles detected a total of 1,487 compounds of known identity. After excluding metabolites with missing values in more than 20% of the samples and with small standard variation, we observed a distinct cluster of participants from AA aggressive PCa patients and current smokers that were separated from EAs and never smokers. With BH-adjusted p-value &amp;lt; 0.05 and fold change &amp;gt; 2, we identified 10 significantly dysregulated metabolites between AA and EA among high aggressive PCa and current smokers. Further, 36 metabolites between current and never smokers among AA high aggressive PCa were significantly dysregulated, but none of them are annotated as tobacco metabolites. Conclusion: Our study presented distinctive metabolomics profiles specific to AA current smokers who had high aggressive PCa. Furthermore, the distinctive patterns were not driven by the tobacco metabolites, with the potential to identify metabolites that might help to understand the relationships between smoking and aggressive PCa in AA. Citation Format: Se-Ran Jun, L. Joseph Su, Eryn Matich, Ping-Ching Hsu. Distinctive metabolomics profiles associated with African American current smokers who have high aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3680.
Revisiting the disease specificity and nomenclature of ficolin‐1–positive monocyte‐derived dendritic cells in diffuse cutaneous systemic sclerosis: comment on the article by Xue et al
Authors: Marika Sarfati, Laurence Chapuy, Heena Mehta
Journal: Arthritis & Rheumatology (2022)

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Treat-to-target dose reduction and withdrawal strategy of TNF inhibitors in psoriatic arthritis and axial spondyloarthritis: a randomised controlled non-inferiority trial
Authors: Celia AJ Michielsens, Nathan den Broeder, Frank HJ van den Hoogen, Elien AM Mahler, Steven Teerenstra, Désirée van der Heijde, Lise M Verhoef, Alfons A den Broeder
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Tumour necrosis factor inhibitors (TNFi) are effective in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), but are associated with a small (0.6%) increase in serious infection risk, patient burden due to need for self-injection and high costs. Treat-to-target (T2T) tapering might ameliorate these drawbacks, but high-quality evidence on T2T tapering strategies is lacking in PsA and axSpA. Methods We performed a pragmatic open-label, monocentre, randomised controlled non-inferiority (NI) trial on T2T tapering of TNFi. Patients with PsA and axSpA using a TNFi with ≥6 months stable low disease activity (LDA) were included. Patients were randomised 2:1 to disease activity-guided T2T with or without tapering until withdrawal and followed-up to 12 months. Primary endpoint was the difference in proportion of patients having LDA at 12 months between groups, compared with a prespecified NI margin of 20%, estimated using a Bayesian prior. Results 122 patients (64 PsA and 58 axSpA) were randomised to a T2T strategy with (N=81) or without tapering (N=41). The proportion of patients in LDA at 12 months was 69% for the tapering and 73% for the no-tapering group: adjusted difference 5% (Bayesian 95% credible interval: −10% to 19%) which confirms NI considering the NI margin of 20%. The mean percentage of daily defined dose was 53% for the tapering and 91% for the no-tapering group at month 12. Conclusions A T2T TNFi strategy with tapering attempt is non-inferior to a T2T strategy without tapering with regard to the proportion of patients still in LDA at 12 months, and results in a substantial reduction of TNFi use. Trial registration number NL 6771.
Abstract 5525: An Fc-competent bispecific antibody targeting PD-L1 and TIGIT induces strong immune responses and potent anti-tumor efficacy
Authors: Shuang Dai, Weifeng Huang, Zhijun Yuan, Shaogang Peng, Jiayi Si, Chao Wang, Yao Yan, Xiaoniu Miao, Yingda Xu, Joanne Sun, Xiaolin Liu, Andy Tsun, Tianhang Zhai
Journal: Cancer Research (2022)

Abstract Background: TIGIT (T-cell immunoglobulin and ITIM domain), which is primarily expressed on activated and 'exhausted' T and NK cells, is one of the most promising 'next generation' immune checkpoint target. Engagement of TIGIT to its ligands (i.e., PVR and PVRL2) leads to inhibitory signaling in T cells and promotes the functional exhaustion of tumor-infiltrating T lymphocytes. Anti-TIGIT monoclonal antibodies have shown clinical benefit when combined with anti-PD-L1 agents in NSCLC. Here, we describe our novel anti-PD-L1 × TIGIT bispecific antibody (PD-L1 × TIGIT biAb) that blocks both the PD-L1/PD-1 and TIGIT/PVR/PVRL2 pathways and has the potential to exhibit equal clinical benefit compared to current combination therapies. Methods: PD-L1 × TIGIT biAb was engineered with a fully-human IgG targeting TIGIT in a g1-Fc backbone, fused to a VHH at the C-terminus targeting PD-L1. Binding affinities and specificity testing were studied by flow cytometry and biolayer interferometry. The co-binding of the PD-L1 × TIGIT biAb to TIGIT and PD-L1 was detected by ELISA. The immunomodulatory functions of the PD-L1 × TIGIT biAb were evaluated using luciferase reporter cell assays and mixed lymphocyte reaction (MLR) assays in vitro, and human PBMC models in vivo. Results: The PD-L1 × TIGIT biAb binds with high affinity to the extracellular domain of human TIGIT and PD-L1 and can bind to TIGIT and PD-L1 simultaneously. In a competition assay, the PD-L1 × TIGIT biAb efficiently blocked the interaction between TIGIT and PVR/PVRRL2, and likewise PD-L1 to PD-1. The PD-L1 × TIGIT biAb induced higher luciferase signals than the anti-TIGIT or anti-PD-L1 mAbs alone in a luciferase reporter-based cell system and enhanced IFN-γ production in an MLR assay. In vivo, the PD-L1 × TIGIT biAb demonstrates similar anti-tumor efficacy to the combination of anti-TIGIT and anti-PD-L1 mAbs, which is stronger than the single-agents alone. We have also completed GLP-toxicity studies that have shown excellent safety. Conclusion: We have discovered a novel PD-L1 × TIGIT biAb, which induces strong immune responses in vitro and in vivo, supporting its clinical development for the treatment of human cancers. Clinical trials shall be initiating in early 2022. Citation Format: Shuang Dai, Weifeng Huang, Zhijun Yuan, Shaogang Peng, Jiayi Si, Chao Wang, Yao Yan, Xiaoniu Miao, Yingda Xu, Joanne Sun, Xiaolin Liu, Andy Tsun, Tianhang Zhai. An Fc-competent bispecific antibody targeting PD-L1 and TIGIT induces strong immune responses and potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5525.
Abstract 104: Targeting NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic ductal adenocarcinoma: An in silco, in vitro and in vivo approach
Authors: Purnachandra N. Ganji, Gregory B. Lesinski, Bassel F. El-Rayes
Journal: Cancer Research (2022)

Abstract NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme. NQO1 is important for catalyzation, detoxification, and reduction of organic compounds including quinone. Elevated NQO1 expression is associated with increased pancreatic ductal adenocarcinoma (PDAC) growth, and metastasis as well as poor prognosis. BBI 608 is a small molecule that exhibits potential therapeutic properties for PDAC due to its powerful anti-inflammatory and antioxidant properties and ability to regulate multiple signaling pathways. The current study explores the binding capacity and ligand efficacy of BBI608 against NQO1 in PDAC. To observe the molecular properties of BBI608 and to analyze the exact mechanism of NQO1 on PDAC, computational approaches were applied, including molecular docking. This investigation provides a detailed understanding of the interaction between NQO1 and BBI608 and its implication in PDAC therapy. To support this computational analysis, we performed in vitro and in vivo studies. The combination of BBI608 with gemcitabine plus irradiation creates higher cytotoxicity (decreased proliferation, clonogenicity and increased Annexin V positive cells; p&amp;lt;0.001) in PDAC cell lines and the mice bearing subcutaneous PANC-02 and MIA PaCa-2 model. Collectively, this investigation offers mechanistic insight into the cytotoxicity initiated by BBI608 and suggests further investigation of its utility for PDAC therapy is warranted. Citation Format: Purnachandra N. Ganji, Gregory B. Lesinski, Bassel F. El-Rayes. Targeting NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic ductal adenocarcinoma: An in silco, in vitro and in vivo approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 104.
Abstract 534: An ultrasensitive high-plex assay detecting 24 <i>PIK3CA</i> mutations using SAGAsafe® technology and 6-color Crystal Digital PCR™
Authors: Miguel Alcaide, Anthony M. George, Yilun Chen, Cécile Jovelet, Sahbi Ben Kilani, Lao H. Saal, Allison C. Mallory
Journal: Cancer Research (2022)

Abstract Starting from a minimally invasive liquid biopsy sample such as a blood sample, one can determine genetic and biological properties of cancer by measuring circulating tumor DNA (ctDNA). ctDNA measurements require a highly sensitive and reliable detection technology to quantify often low-level genetic aberrations within a high background of wild-type sequences. The focus of this study was to demonstrate the performance of the patented SAGAsafe digital PCR chemistry using 6-color Crystal Digital PCR, by adapting a SAGAsafe assay for a clinically relevant oncogene, PIK3CA. PIK3CA encodes the p110-alpha kinase and is the target of a recently approved drug, alpelisib, for metastatic breast cancer. By combining the power of the SAGAsafe technology with that of 6-color Crystal Digital PCR on the naica system®, we present a highly multiplexed, ultrasensitive proof-of-concept PIK3CA detection assay capable of detecting and quantifying 24 PIK3CA mutations in a single digital PCR reaction. By evaluating the sensitivity, specificity and precision of the high-plex 6-color PIK3CA digital PCR assay, we show that despite the complexity of the assay, the data were extremely clean resulting in highly accurate quantifications down to mutant allele frequencies (MAFs) in the 0.01% range. In addition, superb PIK3CA mutation detection specificity and sensitivity were observed with Limits of Blank ranging from 0.003% to &amp;lt;0.001% MAF, and Limits of Detection ranging from 0.009% to 0.002% MAF in a high background of wild-type DNA. Moreover, a high concordance was observed between Crystal Digital PCR PIK3CA results and NGS data on breast cancer biopsies. By joining 6-color Crystal Digital PCR and ultrasensitive SAGAsafe technology, high sensitivity and specificity can be maintained even in a complex multiplex digital PCR assay. This proof-of-concept assay sets the stage for the future development of ultrasensitive, highly multiplexed cancer detection panels to achieve better patient stratification and monitoring during therapy. Citation Format: Miguel Alcaide, Anthony M. George, Yilun Chen, Cécile Jovelet, Sahbi Ben Kilani, Lao H. Saal, Allison C. Mallory. An ultrasensitive high-plex assay detecting 24 PIK3CA mutations using SAGAsafe® technology and 6-color Crystal Digital PCR™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 534.
Abstract 2751: The modular Tmod dual_receptor system exploits tumor deletions to achieve robust tumor-selective cytotoxicity
Authors: Han Xu, Agnes Hamburger, Yuta Ando, Grace Asuelime, Kristian Bolanos, Mark Daris, Breanna DiAndreth, Maria C. Imun, Wen-Hua Lee, Chuck Z. Li, Breanna Luna, Diane Manry, Aaron D. Martin, Michele E. McElvain, Jee-Young Mock, Martin Naradikian, Mark L. Sandberg, Julyun Oh, Sanam Shafaattalab, Shruti Sharma, Talar Tokatlian, Xueyin Wang, Lu Min Wong, Alexander Kamb
Journal: Cancer Research (2022)

Abstract We set out to examine the behavior in preclinical models of a dual-receptor cell therapy approach (Tmod࣪ system) designed to exploit instances of somatic LOH in cancer that can be readily identified through molecular diagnostics. We utilized quantitative pharmacologic assays in vitro and dual-flank efficacy/selectivity models in vivo to test the activity of a variety of constructs comprised of: (i) CAR “activators” that target tumor-associated antigens (TAAs) such as CEA, MSLN and others; and, (ii) LIR-1-based “blockers” that target HLA class I proteins. We generated substantial datasets around multiple targets, including well known tumor-associated antigens (TAAs). In the presence of the HLA class I blocker antigen, Tmod cells were OFF within a wide range of activator antigen expression levels on the “normal” target cells. They were ON when tumor cells expressed the TAA without the HLA blocker antigen, and killed tumor cells selectively even in mixed tumor-normal cell populations. The Tmod system transformed imperfect TAAs into true tumor-selective targets, where the activity of the engineered T cells is controlled by the presence/absence of the HLA blocker antigen. The system was sufficiently modular to use with autologous and allogeneic products. Several of these Tmod constructs are advancing to the clinic where a robust genetic selection tool is being used to screen patients for treatment and match them with a suitable Tmod therapy. In summary, Tmod is a robust system with quantitative pharmacologic behavior in preclinical models consistent with efficacy and safety across a range of targets. Citation Format: Han Xu, Agnes Hamburger, Yuta Ando, Grace Asuelime, Kristian Bolanos, Mark Daris, Breanna DiAndreth, Maria C. Imun, Wen-Hua Lee, Chuck Z. Li, Breanna Luna, Diane Manry, Aaron D. Martin, Michele E. McElvain, Jee-Young Mock, Martin Naradikian, Mark L. Sandberg, Julyun Oh, Sanam Shafaattalab, Shruti Sharma, Talar Tokatlian, Xueyin Wang, Lu Min Wong, Alexander Kamb. The modular Tmod dual_receptor system exploits tumor deletions to achieve robust tumor-selective cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2751.
Abstract 219: Towards targeted-gold nanoparticle enhanced chemoradiation therapy of pancreatic cancer
Authors: Rao V. Papineni, Amitava Adhikary, Santanu Bhattacharya
Journal: Cancer Research (2022)

Abstract The goal of this project is to develop a unique pancreatic cancer treatment platform where, X-ray excited Targeted-Gold nanoparticles (T-GNPs) trigger and enhance drug action (I-RaGAZ, Integrated radiation combined with T-GNP and 2-Azido-2-deoxy-D-glucose (2-AZ-2-DG)). Herein, we plan to utilize a novel three stage nanotechnology-chemoradiation combinatorial approach for enhancing catastrophic cell death in pancreatic tumors and reducing normal tissue toxicity. T-GNP has cytotoxic effect at tumor site and can specifically sensitize tumor tissue for radiation. In this work, we used our GNP-based pancreatic ductal adenocarcinoma (PDAC) -specific drug delivery platform using a plectin-1-targeting peptide (PTP) (patent: US2018/0333432 A1) to demonstrate the cytotoxicity of the nanocomplex in vitro. In PANC-1 cancer cell model, using traditional gold-standard clonogenic assay, we show 2-AZ-2-DG has radiation-mediated cytotoxicity which is further augmented by T-GNP. These results align with our hypothesis and the electron spin resonance (ESR) spectroscopy electron-induced aminyl radical production data presented here. This radiation-produced auger electrons from T-GNP likely increased formation of RNH• which result in enhanced cell kill. This via H-atom abstraction reactions that might cause DNA-strand breaks and/or crosslink formation leading to lesions that could induce apoptosis of cancer cells. This nanotool paraphrased as I-RaGAZ, Integrated radiation induced T-GNP - 2-AZ-2-DG anti-tumor action, will be very useful for treating deep-seated tumors with minimum collateral damage. This approach, integrated radiation-mediated azido tumor cure (I-RaGAZ), has vast global cancer treatment potential considering the dual mode of damaging the tumor tissues and protecting the normal tissues/organs. Citation Format: Rao V. Papineni, Amitava Adhikary, Santanu Bhattacharya. Towards targeted-gold nanoparticle enhanced chemoradiation therapy of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 219.
Abstract LB059: Subtype classification of pediatric high-grade glioma tumors by comparative transcriptomics
Authors: Gina D. Mawla, A. Geoffrey Lyle, Ellen T. Kephart, Katrina Learned, Holly C. Beale, Joshua E. Goldford, Olena M. Vaske
Journal: Cancer Research (2022)

Abstract Pediatric high-grade glioma (pHGG) is a highly malignant and poorly understood cancer driven by diverse genetic and epigenetic mechanisms. Here, we use comparative RNA sequencing, outlier analysis, and spectral clustering approaches to analyze transcriptomic data of 1,543 pediatric brain tumor specimens from the UCSC Treehouse Childhood Cancer Initiative (Treehouse) and Open Pediatric Brain Tumor Atlas (OpenPBTA) to identify subpopulations of pHGG patients with characteristic gene expression profiles. We find that approximately half (45%) of pHGG tumors from OpenPBTA exist in three subgroups defined by high outlier-level expression either of: mitochondrially-encoded 12S and 16S rRNAs; genes enriched in the HSF1-mediated heat shock response and activation pathways; or six C/D box snoRNA (SNORD) genes originating from the paternally-expressed SNORD116 locus involved in Prader-Willi syndrome, a complex neurodevelopmental disorder. Interestingly, the same set of HSF1-dependent pathway genes is also significantly upregulated in a subset (~11%) of pHGG tumors from Treehouse, validating this finding in two independent compendia with different transcript isolation strategies (Treehouse, polyA selection; OpenPBTA, ribodepletion). Our work identifies distinct classes of tumors with outlier-level expression of genes with previously unknown roles in pHGG and provides a framework for subtyping tumors by comparative transcriptomics that is adaptable to any cancer type. We are currently investigating the molecular roles of HSF1-response genes and the imprinted SNORD116 gene cluster in pHGG. Our ongoing research into the biomolecular signatures and mechanisms of the three major tumor classes of pHGG as defined in our study will contribute to a greater understanding of pHGG disease manifestation and progression, and will inform strategies of tailored therapeutic interventions for children with this devastating disease. Citation Format: Gina D. Mawla, A. Geoffrey Lyle, Ellen T. Kephart, Katrina Learned, Holly C. Beale, Joshua E. Goldford, Olena M. Vaske. Subtype classification of pediatric high-grade glioma tumors by comparative transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB059.
Abstract 2056: PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2
Authors: Judith A. Varner, Anghesom Ghebremedhin
Journal: Cancer Research (2022)

Abstract Solid tumors are characterized by extensive immune suppressive inflammation, vascular leak, fibrosis and organ damage. Similarly, SARS-CoV-2 infections induce aberrant pulmonary and systemic inflammation, vascular leak, coagulation, fibrosis and fatal organ damage. We previously demonstrated that macrophages in solid tumors strongly expressed phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinately controls granulocyte and monocyte trafficking to tumors as well as wound-healing-type macrophage transcription in cancer and fibrosis. We also observed that macrophages in COVID-19 lungs strongly expressed PI3Kγ. To identify therapeutic strategies to suppress COVID-19-associated inflammation, we characterized lung tissue of COVID-19 patients using multiplex immunohistochemistry and tissue transcriptomics. Lungs of deceased patients exhibited substantial infiltration by neutrophils and wound-healing macrophages, fibrosis and alveolar type II cell depletion. In animal models of lung inflammation, bacterial infections, viral infection and SARS-CoV-2 infection, PI3Kγ deletion or inhibition with the cancer therapeutic IPI-549 (eganelisib) suppressed pulmonary and systemic inflammation, reduced lung damage, and promoted survival. These studies demonstrate the essential role of PI3Kγ in inflammatory diseases as well as cancer and support the use of PI3Kγ inhibitors such as eganelisib to suppress inflammation and promote survival in pulmonary infections like SARS-CoV-2 and cancer. Citation Format: Judith A. Varner, Anghesom Ghebremedhin. PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2056.